Indole-based compounds as potential drug candidates for SARS-CoV-2

1. Introduction

2. Repurposed indole-containing drugs

2.1. Umifenovir (Arbidol)

Umifenovir (Arbidol) (Figure 8) is a broad-spectrum antiviral drug with inhibitory properties against both RNA and DNA viruses such as Zika, influenza, hepatitis (HBV, HCV), ebola, West Nile and herpes viruses.^94,95 It is one of the drugs that has been repurposed against COVID-19 and has IC₅₀ = 4.11 μM against SARS-CoV-2 [96]. It acts through inhibition of the lipid envelope thereby limiting contact and hence the fusion of the viral cell (membrane fusion inhibitor) with the host/human cell (targeting S-protein/ACE2 “angiotensin-converting enzyme 2”) [97‒100]. Computational studies including molecular docking (PDB ID: 6LZG) [101] and molecular dynamics [102,103] support the mode of action. Antioxidant properties of Arbidol have also been reported to be attributed to its ability to react with free radicals. This may indicate that the anti-SARS-CoV-2 bio-properties of Arbidol are arising from several biochemical pathways [94]. Clinical studies have confirmed the suitability of Arbidol as a monotherapy or in combination with other therapeutics for COVID-19 patients [104‒114]. Some countries (e.g., Russia, China, and Iran [95]), have awarded licenses to Arbidol for the prevention or treatment of COVID-19 [115].

A series of Arbidol analogs 1‒8 have been synthesized starting from 5-hydroxy-2-methylindole-3-carboxylate (Scheme 1). Potential binding of the compounds with the spike glycoprotein (S-protein, ACE2 binding) was determined (Figure 9) revealing no inhibition rates greater than 20%. Some inhibitory properties at low concentrations were higher than others but this can be explained in terms of the low solubility of the compounds in aqueous medium [96].

Arbidol analogs have also been designed, through in-silico studies using Schrodinger software, as inhibitors of ACE2, which is the key receptor that facilitates the entrance of the SARS-CoV-2 virus into the host cell (PDB ID: 6LZG) in addition to the proteases like furin (PDB ID: 5MIM), TMPRSS2 (transmembrane protease serine 2), TMPS2 human and 3CL^pro (3 chymotrypsin-like protease, PDB ID: 6LU7) which are essential for the viral replication. This approach may enable the optimization of multi-targeted inhibitor agents with potential efficacy against COVID-19, but the lack of experimental bio-properties data limits the progress [116] (Figure 10).

Figure 9. Inhibitory properties of Arbidol analogs 1‒8.

Figure 9. Inhibitory properties of Arbidol analogs 1‒8.

2.2. Indomethacin

Indomethacin (Figure 7) is a (non-steroidal anti-inflammatory (NSAID), and analgesic drug used globally.^29,117,118 It works through non-selective inhibition of cyclooxygenase (COX), which is the key enzyme to produce prostaglandin from arachidonic acid. Prostaglandin is responsible for inflammation and pain [119]. Inflammation is a natural response of the human body due to harmful effects. It is associated with many diseases, including microorganism (bacterial/viral) infections, cancers, and asthma [90].

Although indomethacin does not inhibit replication of SARS-CoV-2 (infected Vero E6 bio-assay), studies have reported its potential as a co-treatment for COVID-19 patients due to its potent efficacy against symptoms associated with the disease [120‒124]. Some Indomethacin-Remdesivir conjugates-based proteolysis-targeting chimeras (PROTAC) have been reported with enhanced properties against SARS-CoV-2/NL/2020 and SARS-CoV-2/Padova/2021 strains relative to the parent indomethacin [121] (Figure 11). Conjugation between these mentioned drugs, or any other similar agents, can be a useful approach for optimizing promising hits/leads against SARS-CoV-2.

2.3. Lufotrelvir (PF-07304814)

Lufotrelvir (PF-07304814) (Figure 12) is a SARS-CoV-2 main protease (M^pro) inhibitor developed by Pfizer for intravenous application. The phosphate group is cleaved in-vivo liberating PF-00835231, the effective agent against various viral strains [125].

2.4. Obatoclax (GX15-070)

Obatoclax (GX15-070) (Figure 13) is an antitumor agent (leukemia, lymphoma, and lung) via BCL-2 protein inhibition inducing mitochondrial apoptosis and has been subjected to Phase II clinical trials. It was repurposed for COVID-19 due to its promising properties against ACE2 thereby blocking cellular entry by the infectious virus [126].

3. Natural indole-containing compounds

3.1. Melatonin

Melatonin is a natural hormone biosynthesized from tryptophan primarily by the pinealocytes of the pineal gland in the brain in the dark (hormone of darkness) and transferred by blood to the body organ from the cerebrospinal fluid. It exerts several biological properties [127‒131] (Figure 14). The correlation between the COVID-19 fatalities in the elderly with the decrease in melatonin secretion rate drew attention to a possible application of the hormone for treatment [132]. The ability of melatonin as an anti-oxidant and anti-inflammation also suggested a potential role as an anti-SARS-CoV-2 [133]. Due to its safety profile and diverse bio-properties, numerous reports have considered the role for melatonin in the prevention and treatment of COVID-19 [134‒139]. Clinical studies/observations have supported its ability to reduce the severity of the disease, shorten the hospitalization period or lead to complete recovery upon administration, either as a mono-therapeutic [137‒139] or with other therapeutics, for COVID-19 infected patients [134‒136].

3.2. Neoechinulin A, echinulin and eurocristatine

The natural compounds neoechinulin A, echinulin, and eurocristatine (Figure 15) can be obtained from organisms such as Aspergillus fumigatus MR2012. Neoechinulin A and echinulin have M^pro-SARS-CoV-2 inhibitory properties (IC₅₀ = 0.47, 3.90 μM, respectively) [140]. For comparison, the value is (IC₅₀ = 0.36 μM) for GC376 which is a potent M^pro-SARS-CoV-2 inhibitor [141].

Neoechinulin B 11 can be extracted from Eurotium rubrum Hiji025. It has been synthesized in a two-step reaction involving the 2-indole aldehyde 9 and the appropriate 2,5-piperazinedione 10 in basic conditions followed by tetra-n-butylammonium fluoride. Alternatively, 11 could be obtained from the aldehyde 9 and 2,5-piperazinedione 12 in the presence of piperidine at 110 °C (Scheme 2). Neoechinulin B 11 has anti-SARS-CoV-2 properties (Vero E6, assay, IC₅₀ = 32.9, CC₅₀ = >70 μM) [142].

4. Synthetic indole-containing compounds

4.1. Isatins

A series of isatin derivatives 13 have been synthesized through the reaction of aromatic amines with hydroxylamine hydrochloride (NH₂OH.HCl) and chloral hydrate [Cl₃CCH(OH)₂] followed by cyclization with concentrated sulfuric acid (H₂SO₄) at 90 °C and alkylation (Scheme 3). Some of the synthesized isatin analogs 13 revealed 3C-like protease (3CL^pro) [or main protease (M^pro)] SARS-CoV-2 inhibitory properties relative to Tideglusib (positive control) [143] (Figure 16).

4.2. 2-[(Indol-3-yl)thio]acetamides

2-[(Indol-3-yl)thio)acetamides 14 were synthesized through the reaction of indole derivatives with Bunte salt ethyl acetate-2-sodium thiosulfate in iodine/DMSO at 60 °C followed by hydrolysis (NaOH, EtOH/H₂O) and coupling with the appropriate amine (Scheme 4). Some of the synthesized agents exhibited RdRp inhibitory properties relative to Remdesivir [144] (Figure 17). Considering these observations (Figure 17) and those mentioned in Figure 16, it can be concluded that the substituent attached to the indolyl heterocycle plays a circular role in the mode of action. Compounds of Figure 16 exhibited 3CL^pro inhibitory properties. However, those of Figure 17 revealed RdRp inhibitory properties. So, the mutual mode of action may be optimized by manipulating the substitution of indolyl heterocycle for assigning potent anti-SARS-CoV-2 agents.

A set of acetamide-containing indoles with possible RdRp SARS-CoV-2 inhibitory properties have been explored. The efficacy of the most promising agents was comparable to that of Remdesivir (EC₅₀ = 1.05 μM) [145] (Figure 18).

4.3. Indole chloropyridine conjugates

A variety of indole chloropyridine conjugates 15 were synthesized via reaction of the appropriate indolecarboxylic acid with 3-chloropyridin-5-ols or 5-amino-3-chloropyridines using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and dimethylaminopyridine (DMAP) in methylene chloride (CH₂Cl₂) (Scheme 5). Anti-SARS-CoV-2 activities (Vero E6 assay) with 3CL^pro inhibitory properties were observed for some of the synthesized agents [59] (Figure 19).

Indomethacin-chloropyridine conjugate 16 (Figure 20) is also possible by utilizing the same reaction conditions (EDC and DMAP in CH₂Cl₂, 53% yield). Anti-SARS-CoV-2 activity was observed for the compound (EC₅₀ against SARS-CoV-2 = 30.2 μM, IC₅₀ against 3CL^pro SARS-CoV-2 = 5.32 μM) [146].

4.4. Diindole-substituted benzimidazole

Condensation of 3-indolealdehyde with o-phenylenediamine under green conditions (in water at 75 °C) in a 2:1 molar ratio afforded the corresponding diindole-substituted benzimidazole 17 (Scheme 6). The synthesized agent revealed 92.4 % cell viability (Verso E6) at 9.0 μM concentration in comparison to 99.23% for Remdesivir at 10 μM. The antiviral properties of 17 were supported by the immunofluorescence assay [147].

4.5. 3-Alkenyl-2-oxindoles

Anti-SARS-CoV-2 3-alkenyl-2-oxindoles 18 and 19 were obtained through acidic dehydration (HCl/EtOH) from the corresponding 3-hydroxy analogs (Schemes 7,8). Some of the synthesized agents showed potent anti-SARS-CoV-2 properties (Figure 21) relative to the standards (IC₅₀ = 29.25, 19.78, 1382, CC₅₀ = 356.4, 377.7, 2633 μM for Hydroxychloroquine, Chloroquine, and Favipiravir, respectively) in the Vero E6 assay [148].

4.6. Spiroindoles

Spiroindoles 20 were synthesized through cycloaddition of azomethine ylide (obtained from sarcosine and isatins) with 3,5-diylidene-4-piperidones (Scheme 9). Promising anti-SARS-CoV-2 properties were shown by some of the synthesized agents in the Vero E6 assay relative to the standards Hydroxychloroquine, Chloroquine, and Favipiravir [149] (Figure 22).

Anti-SARS-CoV-2 spiroindole-containing compounds bearing phosphonate group were recently reported with potential M^pro inhibitory properties, synthesized through azomethine (generated from the reaction of isatin and sarcosine) reaction with the appropriate 3,5-bis((E)-ylidene)-1-phosphonate-4-piperidone [150] (Scheme 10).

It has been noticed through this report (Scheme 10) that the spiroindoles with sulfonyl group (Figure 22) are more promising anti-SARS-CoV-2 agents relative to those with phosphonate group.

4.7. Indole with dual acting proteases inhibitor

Di Sarno [151] reported synthesis of indole-containing compound with potential SARS-CoV-2 protease (M^pro “main protease” and PL^pro “papain like protease”) inhibitory properties (Scheme 11).

5. In-silico predicted anti-SARS-CoV-2 indoles

5.1. SARS-CoV-2 (main protease, M^pro) inhibitor

SARS-CoV-2 main protease (M^pro or 3CL^pro) controls many essential viral processes including maturation, replication, and transcription. This makes it a potential target for optimizing therapeutics against COVID-19 [154,155]. Paxlovid is a prominent protease inhibitor approved by the FDA at the end of 2021 for mild and moderately effected patients. It is a combination of two therapeutics, Nirmatrelvir (3CL protease inhibitor) and Ritonavir (protease inhibitor, therapeutic against HIV/AIDS). Paxlovid is effective at reducing the hospitalization period when administrated at the beginning of COVID-19 symptoms [156‒158].

In this section, representative examples of computationally predicted M^pro SARS-CoV-2 inhibitors will be highlighted. Jayabal et al. reported the synthesis of 3-substituted indoles 21 through a multi-component green synthetic approach via reaction of nitroketene S,S-acetal, diamine-containing compound, 3-formylchromone, and indole in the presence of In(OTf)₃ as a catalyst in refluxing ethanol [62] (Scheme 12). Computationally, some of the synthesized agents showed inhibitory properties for SARS-COV-2 M^pro (PDB: 6LU7) and spike glycoprotein (PDB: 7NX7) utilizing Auto Dock-Vina software (v. 1.1.2). For comparison, Remdesivir binding energy = -7.7, -6.5 kcal/mol is against main protease 6LU7 and spike glycoprotein 7NX7, respectively [62] (Figures 23,24).

Figure 24. Representation of Remdesivir and predicted 3-substituted indoles 21 revealing potential properties against 6LU7.

Figure 24. Representation of Remdesivir and predicted 3-substituted indoles 21 revealing potential properties against 6LU7.

Figure 24. (continued). Representation of Remdesivir and predicted 3-substituted indoles 21 revealing potential properties against 7NX7.

Figure 24. (continued). Representation of Remdesivir and predicted 3-substituted indoles 21 revealing potential properties against 7NX7.

Many mushroom metabolites have potential biological activities. Psilacetin, psilocin, and psilocybine, which are psilocybin-mushroom components, have been subjected to M^pro SARS-CoV-2 docking studies (PDB: 6LU7) utilizing AutoDock and AutoDock vina software. They reveal considerable binding affinity in the protein active site (interaction docking scores = -6.0, -5.4, -5.8 kcal/mol for psilacetin, psilocin, and psilocybine, respectively) [159] (Figures 25,26).

Figure 26. 2D- and 3D-docking interactions of A/B, N3 inhibitor; C/D, psilacetin; E/F, psilocin; and G/H, psilocybine in the active pocket of M^pro SARS-CoV-2 (PDB: 6LU7).

Figure 26. 2D- and 3D-docking interactions of A/B, N3 inhibitor; C/D, psilacetin; E/F, psilocin; and G/H, psilocybine in the active pocket of M^pro SARS-CoV-2 (PDB: 6LU7).

A series of indolyl chalcones have also been explored against M^pro (PDB: 6YB7), spike protein (PDB: 6LZG) and RNA dependent RNA polymerase (PDB: 6M71) in-silico by the blind docking technique utilizing AutoDock Vina v.1.1.2. Some of the results suggested promising inhibitory properties that may help narrow the search for anti-SARS-CoV-2 candidates [160] (Figure 27).

The Schiff bases formed from the condensation of isatin and 2-(1-aminobenzyl)benzimidazole revealed in-silico possible M^pro SARS-CoV-2 inhibitory properties (3CL protease, PDB: 6LU7, AutoDock 4.2 software). The 5-bromo-substituted analog of bis-Schiff base 22 formed from the condensation of 2-(1-aminobenzyl)benzimidazole and the corresponding bis-isatin in ethanol containing a few drops of AcOH at room temperature (Scheme 13) is the most promising [161] (Figure 28).

Figure 28. 2D-docking interaction of Schiff bases and N3 in the active site of M^pro SARS-CoV-2 (PDB: 6LU7).

Figure 28. 2D-docking interaction of Schiff bases and N3 in the active site of M^pro SARS-CoV-2 (PDB: 6LU7).

A set of 2-oxindole derivatives with in-silico M^pro SARS-CoV-2 inhibitory properties were mentioned (PDB ID: 6LU7, Molegro Virtual Docker version 7.0.0 Software, MVD) [162] (Figure 29).

A set of isatin based protease inhibitors were collected from previous publications followed by in-silico high throughput screening in the active pocket of M^pro SARS-CoV-2 (chain-A, PDB: 6M03). The most promising agents were identified based on the observed binding affinities (Figure 30). Searching the Zinc drug-like library for similar analogs followed by virtual screening (AutoDock Vina), identified indole analogs with potential inhibitory properties against M^pro SARS-CoV-2 [72] (Figure 31).

Hattori et al. have also reported the in-silico M^pro SARS-CoV-2 properties (PDB: 6Y2F, Maestro Version 10.7.015) in addition to the in vitro activity (Vero E6 assay) of indole-containing compounds [163] (Figure 32).

2-Indole-containing compounds 23 were obtained through the reaction of indole, furan-2-ylmethylenehydrazine, and appropriate aldehyde in ethanol (Scheme 14). Considerable activity against SARS-CoV-2 spike glycoprotein (PDB: 6WPT, Schrodinger 12.4 software) was observed for some of the synthesized agents [164] (Figure 33).

Figure 33. 2D- docking interaction of indole-containing compounds 23 in the active site of SARS-CoV-2 spike glycoprotein (PDB: 6WPT).

Figure 33. 2D- docking interaction of indole-containing compounds 23 in the active site of SARS-CoV-2 spike glycoprotein (PDB: 6WPT).

5.2. RdRp (RNA-dependent RNA polymerase) inhibitor

The RdRp enzyme is one of the most reliable targets for optimizing potent antiviral therapeutics. This is attributed to its ability to terminate the viral RNA replication in addition to the lack of any similar RdRp in the host cell, thus minimizing off-target effects [9,165].

A computational study has also explored isatin analogs for the identification of promising RdRp SARS-CoV-2 inhibitor agents (PDB ID: 7BTF, AutoDock), and the most promising compounds discovered are exhibited in Figure 34 [166].

6. Conclusion

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